Tumor and Constitutional Sequencing for Neurofibromatosis Type 1

Area of Science:

• Oncology
• Genetics
• Cancer Genomics

Background:

• Neurofibromatosis type 1 (NF1) is a genetic disorder predisposing individuals to various tumors.
• Understanding the genetic alterations in NF1-associated tumors is crucial for diagnosis and treatment.
• Biallelic NF1 variants can arise through multiple mechanisms, including deletions and copy-neutral loss of heterozygosity (LOH).

Purpose of the Study:

• To investigate additional gene variants in tumors from individuals with NF1.
• To detect NF1 second hits using paired germline and somatic sequencing.
• To characterize rare tumor types associated with NF1 through tumor sequencing.

Main Methods:

• Analysis of 529 cancer driver genes across 6,381 tumors.
• Performed NF1 LOH analysis on 391 NF1-mutated tumors.
• Evaluated driver genes by tumor type, including malignant peripheral nerve sheath tumors and gliomas.

Main Results:

• NF1 LOH was observed in 133 of 391 (34%) NF1-mutated tumors.
• Copy-neutral LOH was significantly more prevalent in individuals with NF1 (P < .0001), suggesting somatic intrachromosomal recombination.
• Osteosarcoma in NF1 showed NF1 LOH and concurrent p53 alteration; NF1 second hit data aided in assessing missense variant deleteriousness.

Conclusions:

• NF1-associated tumors exhibit a range of NF1 second hits and a notable prevalence of copy-neutral LOH.
• Further research is needed to elucidate LOH mechanisms and develop strategies for tumor risk mitigation in NF1 patients.